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Mitochondrial pore and synaptic stress in Alzheimer's disease

阿尔茨海默病中的线粒体孔和突触应激

基本信息

批准号：
8264172
负责人：
Heng Du
金额：
$ 9万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8264172
关键词：
AD transgenic mice Address Age Alzheimer&apos s Disease Animals Attenuated Axon Biological Assay Calcium Defect Dendritic Spines Development Energy Metabolism Environment Foundations Generations Genetic Health Hippocampus (Brain)Learning Maintenance Mediating Membrane Membrane Potentials Memory Mentors Mitochondria Mitochondrial Swelling Morphology Mus Neurons Oxidative Stress Oxygen Consumption Pathogenesis Pathology Permeability Play Principal Investigator Property Proteins Research Resistance Respiration Role Stress Synapses Synaptic Transmission Testing Transgenic Mice Vertebral column base career cell motility cyclophilin D density enzyme activity insight mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore mouse model novel novel therapeutic intervention overexpression programs response synaptic failure synaptic function trafficking

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction and synaptic loss are early pathological features of Alzheimer's disease. Recent studies indicate that mitochondrial alterations in AD underlie Abeta-mediated synaptic pathology as evidenced by the observations: 1) significant correlation of mitochondrial dysfunction with synaptic loss in AD; and 2) the protection of mitochondria attenuates Abeta -induced synaptic changes. However, the mechanisms of Abeta -induced mitochondrial dysfunction and the consequent synaptic damages have not fully delineated. Notably, mitochondria in neurons are heterogeneous in their properties. A sub-group of neuronal mitochondria locating at synapses or namely synaptic mitochondria play a pivotal role in maintaining synaptic activity/function due to their physical proximity to synapses. Thus, to elucidate the mechanisms underlying Abeta -potentiated synaptic mitochondrial dysfunction is of great significance to deepen our understanding of the synaptic pathology in the pathogenesis of the AD. In the preliminary studies, we have demonstrated that synaptic mitochondria undergo increased propensity towards cyclophilin D (cypD)-mediated mitochondrial permeability transition pore (mPTP) in the Abeta milieu, transgenic AD mice overexpressing Abeta. Along with these changes, Abeta -insulted synaptic mitochondria underwent respiration defects. In addition, Abeta treatment resulted in decreased axonal mitochondrial density and the loss of synapses in cultured hippocampal neurons. As a contrast, these detrimental effects on synaptic mitochondrial and synaptic alterations were significantly attenuated by the blockade of cypD through genetic depletion of cypD. Thus, I have formulated a hypothesis that cypD-mediated mPTP is a potential mechanism underlying Abeta-induced synaptic mitochondrial dysfunction and synaptic alterations. To address this concept, I will utilize an AD mouse model (APP mice) and a novel genetically manipulated transgenic mouse model (genetic cypD-deficient APP mice) as well as cypD-deficiency hippocampal neuron cultures for the studies proposed in this application. This project contains three aims: 1). to determine the impact of cypD-mediated mPTP on synaptic mitochondrial function in APP mice; 2) to determine the impact of cypD-mediated mPTP on synaptic (axonal) mitochondrial dynamics and motility in Abeta milieus; and 3) to determine whether cypD-mediated synaptic mitochondrial dysfunction contributes to Abeta -induced synaptic alterations in APP mice. Upon the completion of this project, I will determine the involvement of cypD mediated mPTP in Abeta induced synaptic mitochondrial dysfunction, and the impact of cypD mediated mPTP on synaptic mitochondrial dynamics and motility, and synaptic function as well as animal learning/memory ability in APP/ Abeta overexpressing mice. Finding derived from this study will have positive impact on the development of new therapeutic approaches for AD treatment. This project will also serve as a firm foundation of my scientific career to establish a research direction distinct from my mentors' by the combination of synaptic mitochondrial dysfunction and synaptic alterations in AD.